Background: Thyroid cancer is one of the fastest growing cancer diagnoses in the United States. Non-medullary thyroid cancer accounts for 95% of all thyroid cancer cases. Up to 8% of all non-medullary thyroid cancers are hereditary. Familial non-medullary thyroid cancer (FNMTC) is more aggressive than sporadic disease. The best approach for screening at risk family members for FNMTC is unknown. The goal of this project is to determine the natural history and best screening strategy for FNMTC, and to identify susceptibility gene(s) for FNMTC. Summary: This is a prospective study of individuals with or at risk for non-medullary thyroid cancer. Individuals will be studied over time within the context of their families in order to quantify prospective risks of cancers in family members, to establish the natural history of FNMTC, define the spectrum of diseases within the families, to identify precursor states, to try to assess the contribution of genetic and environmental components of risk, and to develop effective screening strategies. Our ongoing analysis of screening at risk individuals shows that the prevalence of thyroid nodules and thyroid cancer is much higher than the general population. The higher prevalence of thyroid neoplasm/cancer in kindreds is even more dramatic in younger members at risk. Our ongoing genetic studies using germline and tumor DNA samples by traditional linkage analysis and whole exome sequencing suggest that this syndrome may be polygenetic. We are continuing to analyze novel candidate susceptibility genes in individual families and their role in cancer initiation. Lastly, we are beginning to cross-validate these candidate SNPs/Indels in a cohort of patients with thyroid cancer to determine their prevalence/role as a cancer susceptibility genes.